SUMMARY The popularity of waterpipe smoking as a behavioral/recreational/social activity is increasing in western countries. Little regulatory science is available to inform the Food and Drug Administration (FDA) on waterpipe tobacco health effects. Appropriate regulatory policy for waterpipe tobacco is currently hindered by the lack of data describing realistic use of these products and the resulting health impacts based on topography, constituents, and toxicology research. Herein, our multidisciplinary team proposes to determine emissions and dosages of waterpipe smoke, and evaluate the effects on pulmonary toxicity. We propose to determine the different topographies that can affect the levels of inhaled constituents, thereby causing pulmonary toxicities. We will test the hypothesis that measures of users' puffing topography generated machine emissions will affect pulmonary toxicities by waterpipe tobacco smoke under realistic conditions versus conventional smoking. To test this hypothesis, we designed three specific aims: (1) determine waterpipe smoking topography and toxicity in users based on naturalistic environment; (2) determine the chemical constituents inhaled by users under realistic usage conditions based on waterpipe smoking topography; and (3) determine the impact of waterpipe smoke on pulmonary toxicity and genotoxicity. The research findings generated from this proposal are expected to provide scientific underpinnings to inform the FDA on the regulation of the manufacture, distribution, and marketing of waterpipe tobacco products to protect public health.